Harlin Helena, Hanson Mikael, Johansson C Christian, Sakurai Daiju, Poschke Isabel, Norell Håkan, Malmberg Karl-Johan, Kiessling Rolf
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
J Immunol. 2007 Oct 1;179(7):4513-9. doi: 10.4049/jimmunol.179.7.4513.
Human NK cells can be divided into CD56(dim) and CD56(bright) subsets. These two types of NK cells respond to different types of stimuli, with CD56(dim) NK cells having direct cytotoxic ability and CD56(bright) NK cells having mainly an immunoregulatory function. We show that the CD16+ CD56(dim) NK subset is characterized by sensitivity to cell death induced by activated granulocytes. We identified hydrogen peroxide (H2O2) as the major effector molecule responsible for the cytotoxic effect of granulocytes on CD56(dim) NK cells, because the ability of granulocytes to kill CD56(dim) NK cells was completely abrogated in the presence of the hydrogen peroxide scavenger catalase. When exposing NK cells to H2O2, CD56(dim) cells showed rapid mitochondrial depolarization and down-regulation of activating NKRs, eventually resulting in cell death, whereas CD56(bright) cells remained unaffected. The difference in sensitivity to H2O2 was mirrored by a difference in intracellular oxidation levels between CD56(dim) and CD56(bright) NK cells, and cell lysates from the latter subset possessed a greater ability to block H2O2-mediated oxidation. Our data may explain the preferential accumulation of CD56(bright) NK cells often seen in environments rich in reactive oxygen species, such as at sites of chronic inflammation and in tumors.
人类自然杀伤细胞（NK细胞）可分为CD56（dim）和CD56（bright）亚群。这两种类型的NK细胞对不同类型的刺激有反应，CD56（dim）NK细胞具有直接的细胞毒性能力，而CD56（bright）NK细胞主要具有免疫调节功能。我们发现CD16 + CD56（dim）NK亚群的特征是对活化粒细胞诱导的细胞死亡敏感。我们确定过氧化氢（H2O2）是粒细胞对CD56（dim）NK细胞产生细胞毒性作用的主要效应分子，因为在过氧化氢清除剂过氧化氢酶存在的情况下，粒细胞杀死CD56（dim）NK细胞的能力完全被消除。当将NK细胞暴露于H2O2时，CD56（dim）细胞显示出线粒体快速去极化和活化性自然杀伤细胞受体（NKR）的下调，最终导致细胞死亡，而CD56（bright）细胞则不受影响。CD56（dim）和CD56（bright）NK细胞对H2O2敏感性的差异反映在细胞内氧化水平的差异上，并且后一个亚群的细胞裂解物具有更强的阻断H2O2介导的氧化的能力。我们的数据可能解释了在富含活性氧的环境中，如慢性炎症部位和肿瘤中，经常看到的CD56（bright）NK细胞的优先积累现象。
